Relationship between cannabis and the immune system The new tendency among researchers points toward cannabinoids having an adaptive immunomodulating effect, instead of a suppressing immune activity Even though cannabis has been used for medical and nutritional purposes for thousands of years, people used to consume because they felt the benefits of it. But they knew nothing else. They used it because they could feel. They experienced how it relieved the pain and calmed down their mood. But now, the researchers are trying to understand more than just the molecular composition of cannabis. They want to know the way it interacts with the biological systems in our organisms. We have seen many fantastic discoveries but the truth is that we don’t know much about this unique plant, especially when it comes to the interaction between marijuana and the immune system. There are studies that state that some cannabinoids like THC and CBD are immunosuppressant. This could explain the relief with autoimmune diseases and chronic inflammation we experience after consuming medical marijuana. Other studies concluded that cannabis consumption increases white blood cells counts in immunodeficiency disorders such as HIV, which suggests it has an immune-boosting effect. The matter becomes more complicated when we think that the effects of marijuana are mainly mediated by the endocannabinoid system, which most researchers think interacts with the whole biological activity, which includes our immune system. The truth is that we have much to discover about the way marijuana affects our immune system. In this article we will try to expose what we know so far. A GLOBAL VISION OF OUR IMMUNE SYSTEM Human beings are always exposed to infections, bacteria and viruses. They all want to harm our organism. If we did not have some kind of defense in our organism, humanity would have been extinct a long time ago. That is why we have our immune system: an incredible net of cells, tissues and organs that keep us healthy. The most important “soldiers” in this constant fight are white blood cells or leukocytes, which are always looking for the enemies. We can divide leukocytes in two groups: A/ lymphocytes (B cells and T cells) which get rid of antigens and help the organism to remember previous attackers. And B: phagocytes that neutralize foreign invaders. Many people know T cells due to their relationship with the HIV virus, which kills them. Because of this HIV patients are severely affected by usually harmless infections. Our immune system is very important to detect malfunctioning cells inside our organism and through the process of apoptosis or cell death, makes sure that these cells cannot grow and, therefore, become tumors. The killing of the cells is an essential factor of any healthy immune system in order to keep a perfect equilibrium between growth and death. For instance, in case too many cells die, we can develop autoimmune diseases. However, if our immune system kills too few, we can develop the perfect environment for cancer. It is a question of balance. THE ENDOCANNABINOID SYSTEM AND THE IMMUNE SYSTEM A perfect immune function implies a perfect balance based on continuous and constant communication between our cells, our tissues and our immune organs. Since the endocannabinoid system was discovered in the 1990s, researchers have discovered another key element. Our endocannabinoid system consists of two main receptors (CB1 and CB2) coupled to proteins, endogenous ligands called endocannabinoids (anandamide and 2-AG), plus the proteins that our endocannabinoids carry and also the enzymes that break them down in the body. The endocannabinoids are generated as they are demanded by our organism, they travel through the cerebral chemical synapse and they modulate the activity of the cells. This is the explanation, in a certain way, of why the ECS (Endocannabinoid System) has been called our regulator of homeostasis, which operates continuously for the maintenance of the biological balance of the body. The ECS regulates many physiological processes, such as immune function and inflammation. Both CB1 and CB2 receptors are located in immune cells. However, there are between 10 and 100 times more CB2 receptors than CB1. Endocannabinoids exert their function on immune cells through the CB2 receptor. Activation of the CB2 receptor produces an anti-inflammatory effect and, therefore, is an objective for the therapy of autoimmune disorders and also neurodegenerative diseases. However, the most generalized medical opinion is that any immunosuppressive activity of the ECS is transient and, in fact, can be canceled when necessary in the presence of an infection. Researchers know that some cannabinoids like THC and CBD have a great impact on our health through the interaction in several ways with the endocannabinoid system. Therefore, it is logical to think that the consumption of medical marijuana will directly affect our immune system. However, researchers are still trying to understand how it happens. CANNABIS AND THE IMMUNE SYSTEM When it comes to cannabis, we are dealing with more than 400 different molecules. These molecules include the most well-known cannabinoids, such as THC and CBD, others more than 100 lesser known cannabinoids, terpenes and a large number of flavonoids, whose composition depends on each cannabis variety. Although most research has been done on individual cannabinoids, especially THC and CBD, we are trying to reach decisive conclusions about how they affect our immune system. Most of the research has focused on THC and CBD. THC binds to the CB2 receptor and activates it, producing an anti-inflammatory effect. Therefore, THC is immunosuppressant. Researchers are convinced that THC has a great future in the treatment of autoimmune diseases such as Crohn’s disease and multiple sclerosis. For its part, CBD, despite its low binding affinity to cannabinoid receptors, is also immunosuppressive and reduces the production of cytokine 3 and also inhibits the function of cells known as T 4. However, there is much more than what has been exposed up to here. There is a new research trend and there is evidence that cannabinoids have an adaptive immunomodulatory effect, rather than the simple ability to suppress immunological activity. CANNABIS AND HIV Medical cannabis is a very effective palliative medicine in the treatment of HIV due to its ability to reduce anxiety, increase appetite and relieve pain. But new research suggests that THC has more properties in the treatment of this disease because it is able to regulate the immune system and improve the health of patients. At first, the research corroborated the idea that THC was an immunosuppressant in HIV, by increasing the viral load and weakening the disease. But more recent research shows that it has immunostimulating effects. In 2011, a study was conducted at the University of Louisiana that showed spectacular results when THC was administered to monkeys, more than 28 days before being infected with SIV, which is the simian version of the virus. THC had a protective effect that extended the life of the monkeys by reducing the viral load. Later in 2014, the same team gave the THC to the monkeys for 17 months before being infected with SIV. Not only did it increase the number of T cells and decrease the viral load, but it also protected the apes against the intestinal damage that the virus produces. These incredible results were also replicated in humans. In a study conducted by researchers at the universities in Virginia and Florida, CD4 and CD8 white blood cells counts were compared in a group of 95 HIV patients, among which there were chronic cannabis consumers. Researchers discovered that both types of infection-fighting immune counts were higher among those who consumed marijuana. This means that cannabis is able to improve our immune systems. CANNABIS, CANCER AND THE IMMUNE SYSTEM Unfortunately, cancer is a disease that will affect many people at some moment in our life. Why does it happen? We don’t know it. But what we know is that most cancers share the same mechanism. Our immune system is prepared to detect malignant cells and, through apoptosis, eliminate those that can become tumors. Unfortunately, cancer cells can trick our immune system and make it work in its favor. Spain and Israel lead the investigation of medicinal cannabis potential. Esther Martínez, a cannabis research scientist at the Complutense University of Madrid (Spain), describes a type of interference between cancer cells and the immune system. “When the tumor contacts the immune cells, it inverts the signal,” explained the scientist at a conference of the CBD Project. “It’s as if they said I’m here and I want you to work for me” And instead of attacking the tumor, it gives signs of survival, so the immune system surrounding the cancer undergoes a change. Tumors have the ability to close the immune system “ Once the immune system is disarmed, the cancer cells grow without any kind of control. Until very recently, the only anti-cancer tools approved were treatments such as chemotherapy, which, although it destroys malignant cells, also destroys healthy cells. The enormous emotion that has caused the antitumor capacity of cannabis, specifically the cannabinoids THC and CBD, is normal. In fact, it was the prestigious colleagues of Esther Martínez at the Complutense University of Madrid, Manuel Guzmán and Cristina Sánchez, the scientists who initiated the investigation of the medicinal properties of cannabinoids in the treatment of cancer through, though not exclusively, the apoptosis. But very little is still known about the relationship between the immune system and cannabinoids in this specific process. One of the problems is that in most preclinical trials human tumors that are grafted into mice are used to prevent rejection of hosts (mice). There are some studies that use immunocompetent mice, such as the 2014 report of Dr. Wai Liu, who studied the effects of THC and CBD on brain tumors when combined with radiation therapy. Dr. Liu, a cannabinoid scientist, not only discovered a significant reduction in tumors, but also little or no immune reaction. Without a doubt it is very good news because cannabinoids can also cause apoptosis in lymphocyte cells, potentially suppressing the immune system. The ability of cannabinoids to strengthen or suppress immunological function gives prestige and credibility to the concept that the endocannabinoid system is involved in immunomodulation, as Dr. Liu said. And it can improve immunity through the suppression of immune cells that are valuable for the containment of cells that kill, based on the immune system. IMMUNOTHERAPY FOR CANCER The lack of absolute certainty about the interaction between cannabinoids and the immune system generates doubts about the use of medical marijuana during immunotherapy. Considered the best treatment against cancer in the future, immunotherapy rebuilds the white blood cells in order to detect and erase cancer in the organism. So far, there has only been one research that studies the way cannabinoids may affect this process. But the results were kind of troublesome. Some patients who took medical marijuana along with the anti-cancer immunotherapy drug at the Rambam Medical Center in Haifa, Israel, had 50% less response, compared to immunotherapy alone. Patients who received high-THC cannabis had a better response to immunotherapy than patients with low THC levels in the products they consumed. No significant change in survival rates was observed. There are some reports from California cancer patients who say that they had more benefits by combining immunotherapy with a low-dose, CBD-rich cannabis oil regime. Moreover, a growing number of preclinical data shows that the combination of CBD and THC with chemotherapy and radiation could produce a good synergistic effect to treat cancer. However, these discoveries haven’t been replicated in human tests. Despite there are no clarity enough about cannabinoids and immunotherapy, researchers think is time to forget the old immunosuppressant label and admit the idea that cannabinoids are bidirectional immunomodulators. This is what Dr. Mariano Garcia de Palau, a Spanish cannabis clinician and member of the Spanish Medical Cannabis Observatory has checked in his experiences. Dr. Mariano Garcia de Palau believes that cannabis is immunosuppressive when there is hyper-immune response. But if it is not like that, cannabis regulates and corrects the immune system in our organism. As a matter of fact, cannabis works like the endocannabinoid system and generates equilibrium in the organism. But what can this implicate if you regularly consume marijuana, have a compromised immune system or you are beginning immunotherapy? You always must ask your doctor about it but in the meantime we can only expect more investigation to continue learning more about the interaction between endocannabinoid system, our immune response, and the cannabinoids.